There is substantial evidence that genetics plays an important role in the etiology of prostate cancer. However, the genetic basis underlying this disease remains poorly understood. It is becoming more apparent that genetic variants in a number of low-penetrance alleles of multiple genes may contribute to prostate cancer risk. Additionally, a growing body of evidence suggests that disruption of the DNA damage-response pathway confer susceptibility to prostate cancer. Indeed, we have demonstrated that germline mutations in CHK2 and p53AIP1 diminish their capacities to respond to DNA damage and increased prostate cancer risk, but more comprehensive and systematic studies are needed. In this study, we propose to systematically test the hypothesis that rare or common genetic variants in the DNA damage-response pathway genes, either individually or in combination, are risk factors for prostate cancer. In Aim 1, we will screen 56 well-documented DNA damage-response genes for non-synonymous variants in blood DNA from 94 prostate cancer patients and 94 unaffected men. In Aim 2, we will test the significance of these variants in a case-control study that uses two sets of previously identified cases - those with a strong family history of prostate cancer (n=498 from 189 families) and those with a reported negative prostate cancer family history (n=499), and a population-based control group (n=558). The controls have been extensively screened for prostate cancer by digital rectal examination, serum PSA measurement, transrectal sonographic imaging, and when indicated, by biopsy. In Aim 3, we will validate the variants in Aim 2 that are associated with either familial or sporadic prostate cancer in an independent sets of cases and controls including 734 familial cases, 462 sporadic cases, and 500 age- matched unaffected control men collected at Johns Hopkins University. At the conclusion of this project, we will have provided important insights into the potential role of a group of genes important in DNA damage-response and generated hypotheses as to how these genes interact with each other in the etiology of prostate cancer. Additionally, by making pairwise comparisons among these three groups of subjects, we will be able to discern whether these genetic variants are more strongly associated with familial or sporadic prostate cancer, similarly associated with both or with neither. The ultimate goal of this project is to identify genetic risk factors of prostate cancer in order to improve our understanding of the etiology of this disease and to provide tools for potential identification of men at increased risk of developing the disease in whom prevention strategies might be targeted.